Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes.
Cyclophilins are a family of proteins that bind cyclosporin A (CsA) and possess peptidyl-prolyl cis-trans isomerase activity. In addition, they are secreted by activated cells and act in a cytokine-like manner, presumably via signaling through a cell surface cyclophilin receptor. More recently, host-derived cyclophilin A (CyPA) has been shown to be incorporated into HIV-1 virions and its incorporation essential for viral infectivity. Here we present evidence supporting a role for viral-associated CyPA in the early events of HIV-1 infection. We report that HIV-1 infection of primary peripheral blood mononuclear cells can be inhibited by: (i) an excess of exogenously added CyPA; (ii) a CsA analogue unable to enter the cells; (iii) neutralizing antibodies to CyPA. Taken together with our observations that recombinant CyPA-induced mobilization of calcium in immortalized, as well as primary, CD4+ T lymphocytes, and that incubation of T cells with iodinated CyPA, followed by chemical cross-linking, resulted in the formation of a high molecular mass complex on the cell surface, these results suggest that HIV-1-associated CyPA mediates an early event in viral infection via interaction with a cellular receptor. This interaction may present a target for anti-HIV therapies and vaccines.
Sherry
B
B
The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Zybarth
G
G
Alfano
M
M
Dubrovsky
L
L
Mitchell
R
R
Rich
D
D
Ulrich
P
P
Bucala
R
R
Cerami
A
A
Bukrinsky
M
M
D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000378:metabolism; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D051379:Mice; D019696:Peptidylprolyl Isomerase / Q000494:pharmacology* / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction; D014779:Virus Replication
D017127:Glycation End Products, Advanced; D011994:Recombinant Proteins; D019696:Peptidylprolyl Isomerase; D002118:Calcium